Chlorpromazine

Source: Wikipedia, the free encyclopedia.
Not to be confused with Chlorpropamide.

Chlorpromazine
Skeletal formula of chlorpromazine
Ball-and-stick model of the chlorpromazine molecule
Clinical data
Trade namesLargactil, Thorazine, Sonazine, others
AHFS/Drugs.comMonograph
MedlinePlusa682040
License data
Pregnancy
category
Routes of
administration		By mouth, rectal, intramuscular, intravenous
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)[3]
  • UK: POM (Prescription only)
  • US: WARNING[2]Rx-only
  • EU: Rx-only[4]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability10–80% (Oral; large interindividual variation)[5]
Protein binding90–99%[5]
MetabolismLiver, mostly CYP2D6-mediated[5]
Elimination half-life30 hours[6]
ExcretionKidney (43–65% in 24 hrs)[5]
Identifiers
  • 3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethylpropan-1-amine
JSmol)
  • CN(C)CCCN1c2ccccc2Sc2ccc(Cl)cc21
  • InChI=1S/C17H19ClN2S/c1-19(2)10-5-11-20-14-6-3-4-7-16(14)21-17-9-8-13(18)12-15(17)20/h3-4,6-9,12H,5,10-11H2,1-2H3 checkY
  • Key:ZPEIMTDSQAKGNT-UHFFFAOYSA-N checkY
  (verify)

Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an

intravenously (injection into a vein).[6]

Chlorpromazine is in the

antihistaminergic properties.[6]

Common side effects include movement problems, sleepiness, dry mouth, low blood pressure upon standing, and increased weight.[6] Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, neuroleptic malignant syndrome, severe lowering of the seizure threshold, and low white blood cell levels.[6] In older people with psychosis as a result of dementia it may increase the risk of death.[6] It is unclear if it is safe for use in pregnancy.[6]

Chlorpromazine was developed in 1950 and was the first antipsychotic on the market.

generic medication.[6]

Medical uses

Chlorpromazine is used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder, as well as amphetamine-induced psychosis.

In a 2013 comparison of fifteen antipsychotics in schizophrenia, chlorpromazine demonstrated mild-standard effectiveness. It was 13% more effective than lurasidone and iloperidone, approximately as effective as ziprasidone and asenapine, and 12–16% less effective than haloperidol, quetiapine, and aripiprazole.[13]

A 2014 systematic review carried out by Cochrane included 55 trials that compared the effectiveness of chlorpromazine versus placebo for the treatment of schizophrenia. Compared to the placebo group, patients under chlorpromazine experienced less relapse during 6 months to 2 years follow-up. No difference was found between the two groups beyond two years of follow-up. Patients under chlorpromazine showed a global improvement in symptoms and functioning. The systematic review also highlighted the fact that the side effects of the drug were 'severe and debilitating', including sedation, considerable weight gain, a lowering of blood pressure, and an increased risk of acute movement disorders. They also noted that the quality of evidence of the 55 included trials was very low and that 315 trials could not be included in the systematic review due to their poor quality. They called for further research on the subject, as chlorpromazine is a cheap benchmark drug and one of the most used treatments for schizophrenia worldwide.[14]

Chlorpromazine has also been used in

AIDS patients have been effectively treated with low doses of chlorpromazine.[17]

Other

Chlorpromazine is occasionally used off-label for treatment of severe

palliation, used in small doses to reduce nausea by opioid-treated cancer patients and to intensify and prolong the analgesia of the opioids as well.[18][20] Efficacy has been shown in treatment of symptomatic hypertensive emergency
.

In Germany, chlorpromazine still carries label indications for

pruritus, and preanesthesia.[21]

Chlorpromazine and other phenothiazines have been demonstrated to possess antimicrobial properties, but are not currently used for this purpose except for a very small number of cases. For example, Miki et al. 1992 trialed daily doses of chlorpromazine, reversing

mice.[22] Weeks et al., 2018 find that it also possesses a wide spectrum anthelmintic effect.[23]

Chlorpromazine is an

Periplaneta americana) octopamine receptor α and tyramine receptor 1.[24]

Comparison of chlorpromazine to placebo[25]
Measured outcome Findings summary Findings range Quality of evidence
Global effects
No improvement (9 weeks – 6 months) 30% less risk of having no improvement in mental state, behaviour and functioning RR 0.7 CI 0.6 to 0.9 Very low (estimate of effect uncertain)
Relapse (6 months – 2 years) 35% less risk of relapse RR 0.7 CI 0.5 to 0.9

Adverse effects

See also: List of adverse effects of chlorpromazine

There appears to be a dose-dependent risk for seizures with chlorpromazine treatment.[26] Tardive dyskinesia (involuntary, repetitive body movements) and akathisia (a feeling of inner restlessness and inability to stay still) are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol[27] or trifluoperazine, and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as risperidone or olanzapine.[28]

Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time.

Comparison of chlorpromazine to placebo[25]
Measured outcome Findings summary Findings range Quality of evidence
Adverse effects
Weight gain 5 times more likely to have considerable weight gain, around 40% with chlorpromazine gaining weight RR 4.9 CI 2.3 to 10.4 Very low (estimate of effect uncertain)
Sedation 3 times more likely to cause sedation, around 30% with chlorpromazine RR 2.8 CI 2.3 to 3.5
Acute movement disorder 3.5 times more likely to cause easily reversible but unpleasant severe stiffening of muscles, around 6% with chlorpromazine RR 3.5 CI 1.5 to 8.0
Parkinsonism 2 times more likely to cause parkinsonism (symptoms such as tremor, hesitancy of movement, decreased facial expression), around 17% with chlorpromazine RR 2.1 CI 1.6 to 2.8
Decreased blood pressure with dizziness 3 times more likely to cause decreased blood pressure and dizziness, around 15% with chlorpromazine RR 2.4 CI 1.7 to 3.3

Contraindications

Absolute contraindications include:[5]

  • Circulatory depression
  • CNS depression
  • Coma
  • Drug intoxication
  • Bone marrow suppression
  • Phaeochromocytoma
  • Hepatic failure
  • Active liver disease
  • Previous hypersensitivity (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used.

Relative contraindications include:[5]

Very rarely, elongation of the QT interval may occur, increasing the risk of potentially fatal arrhythmias.[29]

Interactions

Consuming food prior to taking chlorpromazine orally limits its absorption; likewise, cotreatment with

respiratory depression and sedation.[5]

Chlorprozamine is also a moderate inhibitor of

hypoglycaemia (low blood sugar).[5]

Chlorpromazine may also interact with

desferrioxamine may also interact with chlorpromazine to produce transient metabolic encephalopathy.[5]

Other drugs that prolong the QT interval, such as quinidine, verapamil, amiodarone, sotalol and methadone, may also interact with chlorpromazine to produce additive QT interval prolongation.[5]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[30] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[31] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[31] Less commonly, there may be a feeling of the world spinning, numbness, or muscle pains.[31] Symptoms generally resolve after a short period of time.[31]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[32] It may also result in reoccurrence of the condition that is being treated.[33] Rarely, tardive dyskinesia can occur when the medication is stopped.[31]

Pharmacology

Chlorpromazine is classified as a low-potency typical antipsychotic. Low-potency antipsychotics have more anticholinergic side effects, such as dry mouth, sedation, and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol) have the reverse profile.[15]

Pharmacodynamics

Chlorpromazine
Site Ki Species Ref
5-HT1A 3115 Human [34]
5-HT1B 1,489 Human [35]
5-HT1D 452 Human [35]
5-HT1E 344 Human [35]
5-HT2A 2.75 Human [36]
5-HT2C 25 Human [37]
5-HT3 776 Human [38]
5-HT5A 118 Human [35]
5-HT6 19.5 Human [38]
5-HT7 21 Human [35]
α1A 0.28 Human [35]
α1B 0.81 Human [35]
α2A 184 Human [35]
α2B 28 Human [35]
α2C 46 Human [35]
β1 >10,000 Human [35]
β2 >10,000 Human [35]
M1 47 Human [35]
M2 433 Human [35]
M3 47 Human [35]
M4 151 Human [35]
D1 114.8 Human [38]
D2 7.244 Human [38]
D3 6.9 Human [39]
D4 32.36 Human [38]
H1 4.25 Human [39]
H2 174 Human [35]
H3 1,000 Human [39]
H4 5,048 Human [35]
NET 2,443 Human [35]
DAT >10,000 Human [35]

Chlorpromazine is a very effective antagonist of

synaptic cleft. At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.[15]

Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic and presynaptic receptors:

  • Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
  • extrapyramidal side effects
    , but also leading to weight gain and ejaculation difficulties.
  • Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain)
  • α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor as well as with intraoperative floppy iris syndrome due to its effect on the iris dilator muscle.[40]
  • electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).[medical citation needed
    ]

The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.[41]

Chlorpromazine and other typical

D2 receptors. In fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug's affinity for the D2 receptor. Therefore, a larger dose is required if the drug's affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for dopamine receptors.[42]
Chlorpromazine tends to have greater effect at serotonin receptors than at D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is more similar to the atypical antipsychotics than to the typical antipsychotics.[42]

Chlorpromazine and other antipsychotics with

antihistamines.[43]

In addition to influencing the neurotransmitters dopamine, serotonin,

NMDA receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in glutamate and glycine activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.[44]

Chlorpromazine does also act as a FIASMA (functional inhibitor of acid sphingomyelinase).[45]

Peripheral effects

Chlorpromazine is an antagonist to H1 receptors (provoking antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1 and M2 receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).[medical citation needed]

Because it acts on so many receptors, chlorpromazine is often referred to as a "

dirty drug".[46]

Pharmacokinetics

Pharmacokinetic parameters of chlorpromazine[5][15][47]
Bioavailability tmax CSS Protein bound Vd t1/2 Details of metabolism Excretion Notes
10–80% 1–4 hours (Oral); 6–24 hours (IM) 100–300 ng/mL 90–99% 10–35 L/kg (mean: 22 L/kg) 30±7 hours CYP2D6, CYP1A2—mediated into over 10 major metabolites.[15] The major routes of metabolism include hydroxylation, N-oxidation, sulfoxidation, demethylation, deamination and conjugation. There is little evidence supporting the development of metabolic tolerance or an increase in the metabolism of chlorpromazine due to microsomal liver enzymes following multiple doses of the drug.[48] Urine (43–65% after 24 hours) Its high degree of lipophilicity (fat solubility) allows it to be detected in the urine for up to 18 months.[5][49] Less than 1% of the unchanged drug is excreted via the kidneys in the urine, in which 20–70% is excreted as conjugated or unconjugated metabolites, whereas 5–6% is excreted in feces.[49]
Three common metabolites of chlorpromazine

History

Advertisement for Thorazine (chlorpromazine) from the early 1960s[50]

In 1933, the French pharmaceutical company

Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs.[51]: 77  A year later, the French surgeon Pierre Huguenard used promethazine together with pethidine as part of a cocktail to induce relaxation and indifference in surgical patients. Another surgeon, Henri Laborit, believed the compound stabilized the central nervous system by causing "artificial hibernation", and described this state as "sedation without narcosis". He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties.[52] In December 1950, the chemist Paul Charpentier produced a series of compounds that included RP4560 or chlorpromazine.[7]

Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the Val-de-Grâce military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its hypothermic effect and suggested it may induce artificial hibernation. Laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time. Known colloquially as "Laborit's drug", chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name Largactil, derived from large "broad" and acti* "activity".[7]

Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns,

pentothal and ECT) to Jacques Lh. a 24-year-old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.[7]

Pierre Deniker had heard about Laborit's work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Sainte-Anne Hospital Center in Paris where he was Men's Service Chief.[7] Together with the Director of the hospital, Jean Delay, they published their first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents.[53] The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour.[54] They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily.[7]

Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the

Verdun Protestant Hospital in Montreal trialled it in 70 patients and also noted its striking effects, with patients' symptoms resolving after many years of unrelenting psychosis.[55] By 1954, chlorpromazine was being used in the United States to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders.[15][56][57]
Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's
antidepressants.[58]

Chlorpromazine largely replaced electroconvulsive therapy, hydrotherapy,[59] psychosurgery, and insulin shock therapy.[54] By 1964, about 50 million people worldwide had taken it.[60] Chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug although not a perfect one.[25]

Society and culture

In Literature

Thorazine was often depicted in Tom Wolfe's The Electric Kool-Aid Acid Test to abort bad trips on LSD. Thorazine is also mentioned in Fear and Loathing in Las Vegas, where it was reported to have similar effects to those on LSD.

Names

Brand names include Thorazine, Largactil, Hibernal, and Megaphen (sold by Bayer in West-Germany since July 1953).[61]

Research

Chlorpromazine has tentative benefit in animals infected with Naegleria fowleri,[62] and shows antifungal and antibacterial activity in vitro.[63][clarification needed]

Veterinary use

The veterinary use of chlorpromazine has generally been superseded by use of acepromazine.[64]

Chlorpromazine may be used as an antiemetic in dogs and cats, or, less often, as sedative before anesthesia.[65] In horses, it often causes ataxia and lethargy, and is therefore seldom used.[64][65]

It is commonly used to decrease nausea in animals that are too young for other common anti-emetics.[

preanesthetic and muscle relaxant in cattle, swine, sheep, and goats.[citation needed
]

The use of chlorpromazine in food-producing animals is not permitted in the EU, as a maximum residue limit could not be determined following assessment by the European Medicines Agency.[66]

References

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